Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations and is a major health issue in Veterans. Despite numerous pharmacological agents targeting CVD risk factors, the identification of individuals at high risk remains incomplete. Further, there is still a need to identify new targets for therapy. SAA is an acute phase reactant that is significantly and persistently elevated in chronic inflammatory conditions such as diabetes, metabolic syndrome (MetS) or rheumatoid arthritis, which are all associated with increased rates of CVD. SAA has been found to be predictive of CVD events. Furthermore, we and others have recently shown in murine models that increased SAA is directly pro-atherogenic. As described in the Response to Retention hypothesis of atherosclerosis, the sub-endothelial retention of atherogenic lipoproteins by vascular wall proteoglycans initiates atherosclerosis. Although in the healthy state SAA is exclusively associated with HDL, we and others have previously reported SAA in association with apoB-containing lipoproteins in murine models of diabetes and/or obesity and we recently confirmed this observation in human studies. In preliminary studies we demonstrate increased association of SAA with apoB- containing lipoproteins in insulin resistant states, which may be due to the delayed lipoprotein clearance seen with insulin resistance. In new preliminary studies we demonstrate that SAA can shift from HDL to apoB-containing lipoproteins. SAA itself has proteoglycan binding properties and our preliminary data demonstrates that the presence of SAA on apoB-lipoproteins enhances their retention. The central hypothesis of this grant is that the shift of SAA from HDL to apoB-containing lipoproteins is pro-atherogenic. We propose that the presence of SAA on apoB- containing lipoproteins in insulin resistant conditions such as MetS and diabetes contributes to the increased atherosclerosis and CVD observed in these populations. Using in vitro, in vivo, and clinical studies, the results of this proposal will identify that SAA augments the atherogenicity of apoB lipoproteins and thus may identify SAA as a target for therapeutic intervention.
Cardiovascular disease is the leading cause of death in developed nations and is a major health issue in Veterans. The inflammatory marker Serum Amyloid A (SAA) has been found to predict cardiovascular disease. This proposal is testing the concept that beyond predicting cardiovascular disease, SAA may cause cardiovascular disease. The results of this proposal may identify SAA as a new target of risk reducing therapy.